AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress.
AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress.
复制标题
DOI：
10.1152/physiolgenomics.00045.2015
复制
发表时间：
2015-07
影响因子：
4.6
通讯作者：
C. Koczor;Zhe Jiao;Earl J. Fields;Rodney B Russ;Tomika Ludaway;W. Lewis
中科院分区：
文献类型：
--
作者：
C. Koczor;Zhe Jiao;Earl J. Fields;Rodney B Russ;Tomika Ludaway;W. Lewis
线粒体功能障碍会导致氧化应激和心肌病。氧化应激也是双脱氧核苷抗逆转录病毒药物(NRTI)的副作用，并在NRTI诱导的心肌病中观察到。我们在这里表明，用NRTI AZT{1-[(2R，4S，5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2，4-dione}治疗通过产生线粒体衍生的活性氧物种，以表观遗传方式调节心脏基因的表达。将普遍表达线粒体靶向过氧化氢酶(MCAT)的转基因小鼠和C57BL/6野生型小鼠(WT)分别给予AZT(0.22 mg/d，po，35d)，分离心肌DNA和mRNA。在AZT治疗的WTS中，95个心脏基因与赋形剂治疗的WTS相比差异表达。当MCAT小鼠接受AZT治疗时，这95个基因中的每一个都恢复到了赋形剂治疗的WTS的表达。在AZT处理的WT心脏，MTHFR[5，10-亚甲基四氢叶酸还原酶，合成蛋氨酸循环中间体包括S-腺苷蛋氨酸的关键酶]过表达。AZT处理的MCAT小鼠心脏提取物中SAM的稳态丰度比赋形剂处理的MCAT增加了60%。在WT中没有发生这样的变化。AZT导致WT心脏DNA中差异甲基化DNA区域的高甲基化(47%)和低甲基化(53%)。与赋形剂处理的MCAT对照组相比，AZT处理的MCAT心脏DNA显示出更多的高甲基化(91%)和更少的低甲基化(9%)。编码蛋白激酶C-α的基因表现出氧化应激引起的多焦点表观遗传调控。结果表明，心肌线粒体衍生的氧化应激抑制了心肌DNA甲基化，改变了SAM的稳态丰度，改变了心脏基因的表达，促进了心肌病特有的病理生理变化。NRTI毒性的这种机制提供了对这些常用抗病毒药物的长期副作用的洞察。
Mitochondrial dysfunction causes oxidative stress and cardiomyopathy. Oxidative stress also is a side effect of dideoxynucleoside antiretrovirals (NRTI) and is observed in NRTI-induced cardiomyopathy. We show here that treatment with the NRTI AZT {1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione} modulates cardiac gene expression epigenetically through production of mitochondrially derived reactive oxygen species. Transgenic mice with ubiquitous expression of mitochondrially targeted catalase (MCAT) and C57Bl/6 wild-type mice littermates (WT) were administered AZT (0.22 mg/day po, 35 days), and cardiac DNA and mRNA were isolated. In AZT-treated WT, 95 cardiac genes were differentially expressed compared with vehicle-treated WTs. When MCAT mice were treated with AZT, each of those 95 genes reverted toward the expression of vehicle-treated WTs. In AZT-treated WT hearts, Mthfr [5,10-methylenetetrahydrofolate reductase; a critical enzyme in synthesis of methionine cycle intermediates including S-adenosylmethionine (SAM)], was overexpressed. Steady-state abundance of SAM in cardiac extracts from AZT-treated MCAT mice increased 60% above that of vehicle-treated MCAT. No such change occurred in WT. AZT caused hypermethylation (47%) and hypomethylation (53%) of differentially methylated DNA regions in WT cardiac DNA. AZT-treated MCAT heart DNA exhibited greater hypermethylation (91%) and less hypomethylation (9%) compared with vehicle-treated MCAT controls. The gene encoding protein kinase C-α displayed multifocal epigenetic regulation caused by oxidative stress. Results show that mitochondrially derived oxidative stress in the heart hinders cardiac DNA methylation, alters steady-state abundance of SAM, alters cardiac gene expression, and promotes characteristic pathophysiological changes of cardiomyopathy. This mechanism for NRTI toxicity offers insight into long-term side effects from these commonly used antiviral agents.